Biological Relevance:The RAS family of small GTPases comprises a set of highly regulated switches controlling several cellular signal transduction pathways and networks important for growth, cytoskeletal rearrangements, adhesion, motility, viability, and differentiation. Deregulated, constitutively active, mutant RAS proteins are expressed in approximately 30% of human tumors and are oncogenic, as the viability and proliferation of cancer cells harboring these mutations have been shown to be dependent upon mutant RAS. Despite the intense interest in RAS over the last 25 years, the identification of direct low molecular weight modulators of RAS that can be used to probe the basis for the mutant RAS-dependent malignant phenotype and serve as potential lead structures for therapeutic development has proven challenging.

Rather than target mutant RAS protein directly, an alternative approach involves the selective modulation of cellular deregulation that occurs specifically in mutant RAS-dependent cells. Toward this end, employing RNA interference (RNAi) technology in a gene suppression screen, a serine/threonine kinase, STK33, has recently been identified and shown to be required for the survival and proliferation of mutant KRAS-dependent cancer cells irrespective of tissue origin (PMID 19490892). Remarkably, STK33 appears to be dispensable in KRAS-independent cells. These results indicate a co-dependency between mutant KRAS and STK33 that results in a synthetic lethal interaction when STK33 is suppressed. Consistent with the RNAi studies, expressing catalytically inactive STK33 as a dominant negative has shown that STK33 promotes KRAS-dependent cancer cell viability in a kinase activity-dependent manner.

The overall near term goal is to identify STK33 kinase activity inhibitors to assess whether small molecules can recapitulate the exquisite cell-based specificity of RNAi for inducing apoptosis in mutant KRAS-dependent cells without discernable effects on KRAS-independent cells. The longer-term objective is to use these probes in conjunction with a comprehensive proteomics approach to elucidate the molecular basis of RAS-dependent regulation and mutant KRAS-dependent tumorigenesis with the goal of translating this knowledge into a therapeutic opportunity.